Abstract
Background:
Alcohol relapse occurs frequently in alcohol-associated hepatitis (AH) survivors, but data on the frequency and course of recurrent alcohol-associated hepatitis (rAH) are sparse. We investigated the incidence, risk factors, and outcomes of rAH.
Methods:
Hospitalized patients with AH from 2010 to 2020 at a large health care system were followed until death/liver transplant, last follow-up, or end of study (December 31, 2021). AH was defined by NIAAA Alcoholic Hepatitis Consortium criteria; rAH was defined a priori as a discrete AH episode >6 months from index AH hospitalization with interim >50% improvement or normalization of total bilirubin. Multivariable competing risk analysis was performed to identify factors associated with rAH. Landmark Kaplan-Meier analysis was performed to compare survival between patients who did versus those who did not develop rAH.
Results:
Of 1504 hospitalized patients with AH, 1317 (87.6%) survived and were analyzed. During a 3055 person‐year follow‐up, 116 (8.8%) developed rAH at an annual incidence rate of 3.8% (95% CI: 2.8–4.8). On multivariable competing risk analysis, marital status [sub-HR 0.54 (95% CI: 0.34, 0.92), p=0.01] and medications for alcohol use disorder [sub-HR 0.56 (95% CI: 0.34, 0.91), p=0.02] were associated with a lower risk for rAH. On landmark Kaplan-Meier analysis, the cumulative proportion surviving at 1 year (75% vs. 90%) and 3 years (50% vs. 78%) was significantly lower in patients who developed rAH compared to those who did not develop rAH (log-rank p<0.001).
Conclusions:
rAH develops in ~1 in 10 AH survivors and is associated with lower long-term survival. Medications for alcohol use disorder lower the risk for rAH and, therefore, could be a key preventative strategy to improve outcomes.
INTRODUCTION
Alcohol use disorder (AUD) has emerged as a major public health concern with significant medical and socioeconomic consequences.1 AUD can lead to a spectrum of liver injury, which is broadly classified as alcohol-associated liver disease (ALD)2 and includes hepatic steatosis with or without fibrosis, cirrhosis, and alcohol-associated hepatitis (AH).2 AH is the most severe form of ALD, characterized by rapid onset of jaundice, elevated liver enzymes, and coagulopathy.3
AH requiring hospitalization is associated with high short-term mortality, which may be improved by corticosteroids.4 Corticosteroids are beneficial to individuals meeting severe AH criteria [Model for End-stage Liver Disease (MELD) score >20 or Maddrey discriminant function >323,4]; however, they have not been shown to improve long-term survival.5 The most effective treatment found to improve long-term survival in patients with AH is complete abstinence from alcohol.6 Unfortunately, most patients with AH return to drinking alcohol,6 which could lead to subsequent or recurrent alcohol-associated hepatitis (rAH).
To date, only few studies have described rAH.7–9 These studies, however, were limited by small sample size, varying definitions of AH, incomplete clinical characteristics, and follow-up. With the rising prevalence of AH coupled with improved survival rates,10 it is likely that clinical burden of rAH will increase, contributing to significant health care costs and utilization. That said, a better understanding of the incidence and outcomes associated with rAH would be prudent to improve care after AH hospitalization, prognostication, and importantly, development of interventions to prevent rAH. Thus, the aim of this study was to describe the incidence, clinical characteristics, risk factors, and outcomes associated with rAH in a large cohort of patients with AH hospitalized at multiple hospitals within a large health care system in the United States.
METHODS
Study population
Consecutive patients 18 years of age or above hospitalized with an International Classification of Diseases (ICD) ninth and 10th revision diagnosis codes for ALD (see Supplemental Table S1, http://links.lww.com/HC9/A686 for ICD-9 and 10 codes) within the Indiana University Health Hospital system [11 hospitals, 1 liver transplant (LT) center] from January 1, 2010, to December 31, 2020, were retrospectively reviewed for AH. AH was defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Alcoholic Hepatitis Consortia criteria for “probable AH”3: active alcohol use (>60 g of alcohol per day for men and >40 g of alcohol per day for women) for 6 months or more with <60 days of abstinence before the onset of jaundice, serum aspartate transaminase >50 IU/mL, aspartate transaminase to alanine aminotransferase ratio >1.5, total bilirubin >3.0 mg/dL, and without any confounding factors (eg, ischemic hepatitis, DILI). Severe AH was defined by an admission MELD score >20.3 Information on alcohol intake at the time of index AH and rAH hospitalization (see “Definitions: Recurrent AH and Alcohol Relapse) was obtained from electronic medical records within Indiana University Health System (ie, documentation from physicians and social workers) that was provided by the patient or their family/power of attorney if incapacitated. Information on alcohol intake was also obtained from the Indiana Network for Patient Care (INPC), which contains more than 3 billion pieces of clinical data (eg, clinical notes, laboratory, medications, death date) within various health systems in the state of Indiana.11 We excluded patients if they did not meet AH criteria, had inadequate laboratory data to determine AH, or had prior solid organ transplantation. For patients with multiple qualifying ALD-related hospitalizations during the study period, we considered the initial AH hospitalization as the index AH episode. In addition, for the purposes of the current study, we further excluded patients who died during their index AH hospitalization. This study was approved by the Indiana University Institutional Review Board and is in accordance with both Declarations of Helsinki and Istanbul. Informed consent was waived as this was a retrospective study.
Definitions of recurrent AH and alcohol relapse
We defined rAH a priori as a discrete episode of AH meeting NIAAA criteria for “probable AH” >6 months from the index AH hospitalization with documented interim normlization of total bilirubin or >50% improvement in total bilirubin between the index AH hospitalization and rAH hospitalization. A minimum of 6 months between index AH and rAH hospitalization was chosen because after a period of abstinence, a minimum of 6 months of heavy alcohol use is required to meet NIAAA AH criteria.3 We defined alcohol relapse as any amount of regular alcohol use (consumption at least once a week) after index AH hospitalization.6 Alcohol relapse was further dichotomized into “slip,” defined as an episode of brief alcohol use with regained abstinence after index AH hospitalization or “hazardous drinking,” defined as >60 g of alcohol intake per day for men and >40 g of alcohol intake per day for women for 6 months or more3 after index AH. The amount of alcohol was determined by how many standard drinks a patient consumed. We used the NIAAA definition for a standard drink, where 1 standard drink (12 ounces of beer, 5 ounces of wine, and 1.5 ounces of distilled spirit) equaled 14 g of alcohol.3
Index and recurrent AH hospitalization details
Demographic details, insurance type, vital signs, and laboratory data (white blood cell count, sodium, albumin, liver enzymes, creatinine, total bilirubin, prothrombin time, international normalized ratio) were obtained. History of anxiety and depression medication use (Supplemental Table S2, http://links.lww.com/HC9/A686) and corticosteroid use (prednisone, prednisolone, or methylprednisone) were obtained. In addition, information on cirrhosis and liver-related complications, infections, and comorbidities were obtained using previously validated ICD-9/10 codes (primary or secondary, summarized in Supplemental Table S1, http://links.lww.com/HC9/A686).12–14 The diagnosis of cirrhosis was further verified by means of manual chart review and was based on clinical parameters including laboratory tests, endoscopic or radiologic evidence of cirrhosis, evidence of decompensation (HE, ascites, and variceal bleeding), and liver biopsy where available. Information on acute kidney injury (AKI), as defined by the International Club of Ascites15, was obtained. Moreover, we captured if a patient was treated for alcohol withdrawal, admitted to the intensive care unit, and had vasopressor, mechanical ventilation, or acute hemodialysis use.
Follow-up and outcomes
Patients were followed from the time of admission until death, LT, date of last follow-up, or end of study (December 31, 2021). The primary outcome was rAH hospitalization from the time of discharge. During the follow-up period, alcohol relapse, medications for alcohol use disorder (MAUD)2 (naltrexone, acamprosate, gabapentin, baclofen, and topiramate), enrollment into alcohol rehabilitation, gastroenterology/hepatology subspeciality clinic follow-up, and survival were captured through electronic medical chart review within the Indiana University Health System or the INPC.
Statistical analysis
Clinical and demographic characteristics at the time of index AH hospitalization between patients who developed rAH and those who did not were compared. In patients with rAH, similar comparisons were made between the index hospitalization and rAH hospitalization. Continuous variables were presented as mean ± SD and median with interquartile range (IQR) where it was appropriate. Categorical variables were presented as percentages. In independent samples, differences between categorical variables were analyzed using chi-square or Fisher exact tests, whereas continuous variables were analyzed using Student t tests or Wilcoxon rank sum tests. In paired sample analysis, McNemar paired chi-square and t tests were used to analyze categorical and continuous variables, respectively.
Survival was estimated in patients with (ie, slip, hazardous drinking) and without alcohol relapse and rAH using the Kaplan-Meier method and compared using the log-rank test. To account for immortal time bias related to different exposure times for alcohol relapse and rAH, a landmark analysis was performed,16 where relapse and rAH were defined at 6 months/1 year and 1 year/2 years (landmark times) from index AH discharge, respectively, and all patients with outcomes (mortality or LT) prior to that time and those with relapse or rAH after that time were excluded. The cumulative incidence of alcohol relapse and rAH was estimated from the time of index AH discharge using Fine and Gray competing risk regression. Death and LT during the follow-up period were considered as competing risks, and patients lost to follow-up were censored at the time of the last clinical encounter. Univariate competing risk analysis was performed to identify risk factors associated with alcohol relapse and rAH. Significant variables (p<0.1) were then entered into a multivariable competing risk model to determine the independent association of each risk factor for alcohol relapse and rAH. Subhazard ratio (sHR) and their corresponding 95% CI were reported. A two-sided nominal p-value < 0.05 was considered statistically significant. All analyses were performed using STATA 17 (STATA Corp, College Station, TX) and SAS v9.4 (SAS Institute, Cary, NC).
RESULTS
Cohort Characteristics
A total of 1504 unique patient hospitalizations met NIAAA definition for probable AH (Supplemental Figure S1, http://links.lww.com/HC9/A687), of which 187 patients (12.4%) died during the index AH hospitalization, leaving 1317 (87.6%) patients for analysis. Patients who died during index admission were older, had higher MELD scores and higher frequency of cirrhosis. The characteristics of these patients are shown in Supplemental Table S3, http://links.lww.com/HC9/A686. Overall, the median (IQR) follow-up was 604 (106, 1407) days. Twenty-six patients (2.0%) had a liver biopsy during the index hospitalization. The mean age was 47.9±10.9 years, and the majority were White (n=1170, 88.8%) and male (n=794, 60.3%) (Table 1). The median admission (IQR) MELD and Maddrey discriminant function scores were 22.0 (18.0, 27.0) and 42.6 (25.3, 65.7), respectively; 14.6% were admitted during the COVID-19 pandemic. At the end of the follow-up, 41.5% (546/1,317) died, 3.3% (44/1,317) received an LT, and 10.6% (140/1,317) were lost to follow-up. A minority received AUD pharmacotherapy (n=200, 15.2%) or underwent alcohol rehabilitation (n=77, 5.8%).
TABLE 1.
Comparisons of patient characteristics at index AH hospitalization stratified by subsequent development of recurrent AH
| Total cohort N=1317 | Recurrent AH N=116 | No recurrence N=1201 | p a | |
|---|---|---|---|---|
| Age in years (SD) | 47.9 (10.9) | 44.8 (9.9) | 48.2 (10.9) | 0.002 |
| Race, n (%) | ||||
| White | 1170 (88.8) | 103 (88.8) | 1067 (88.8) | 0.11 |
| Black | 103 (7.8) | 13 (11.2) | 90 (7.5) | — |
| Other | 6 (0.6) | 0 (0) | 7 (0.6) | — |
| Unknown | 38 (2.9) | 0 (0) | 37 (3.1) | — |
| Sex, n (%) male | 794 (60.3) | 63 (54.3) | 731 (60.9) | 0.17 |
| Insurance, n (%) | ||||
| Medicaid | 913 (69.3) | 84 (72.4) | 829 (69.0) | 0.13 |
| Medicare | 198 (15.0) | 11 (9.5) | 187 (15.6) | — |
| Private | 17 (1.3) | 0 (0) | 17 (1.4) | — |
| Self-pay | 189 (14.4) | 21 (18.1) | 168 (14.0) | — |
| Employed, n (%) | 233 (17.7) | 18 (15.5) | 215 (17.9) | 0.14 |
| Marital status, n (% married) | 456 (34.6) | 29 (25.0) | 427 (35.5) | 0.02 |
| Tobacco use, n (%) | 629 (47.8) | 67 (57.8) | 562 (46.8) | 0.62 |
| Anxiety medication, n (%) | 197 (15.0) | 16 (13.8) | 181 (15.1) | 0.71 |
| Depression medication, n (%) | 199 (15.1) | 14 (12.1) | 185 (15.4) | 0.34 |
| Underlying cirrhosis, n (%) | 1,031 (78.3) | 90 (77.6) | 941 (78.4) | 0.85 |
| Hepatitis C, n (%) | 108 (8.2) | 12 (10.3) | 96 (8.0) | 0.39 |
| Diabetes, n (%) | 135 (10.3) | 13 (11.2) | 122 (10.2) | 0.72 |
| Hypertension, n (%) | 222 (16.9) | 28 (24.1) | 194 (16.2) | 0.03 |
| Ascites, n (%) | 355 (27.0) | 28 (24.1) | 327 (27.2) | 0.47 |
| HE, n (%) | 220 (16.7) | 13 (11.2) | 207 (17.2) | 0.10 |
| Body mass index, kg/m2 (SD) | 28.3 (7.0) | 28.3 (6.8) | 28.3 (7.0) | 0.98 |
| Alcohol intake per day, median (IQR) grams | 116 (60, 294) | 112 (60, 350) | 116 (60, 280) | 0.80 |
| MELD, median (IQR) | 19.5 (17, 25.5) | 19.5 (17, 25.5) | 22 (18, 27) | 0.02 |
| MDF, median (IQR) | 35.3 (20.7, 59.8) | 35.3 (20.7, 59.8) | 43.3 (25.9, 66.0) | 0.02 |
| Severe AH, n (%) | 755 (57.3) | 53 (45.7) | 702 (58.5) | 0.01 |
| Corticosteroid use, n (%) | 492 (37.4) | 43 (37.1) | 449 (37.4) | 0.95 |
| Alcohol withdrawal, n (%) | 237 (18.0) | 16 (13.8) | 221 (18.4) | 0.22 |
| Hospital length of stay, median (IQR) | 6 (4, 12) | 6 (4, 11) | 6 (4, 12) | 0.65 |
Comparisons between recurrent AH and no recurrence.
Abbreviations: AH, alcohol-associated hepatitis; IQR, interquartile range; MELD, Model for End-stage Liver Disease; MDF, Maddrey discriminant function.
Alcohol relapse
The median (IQR) time from discharge to alcohol relapse was 192 (48, 551) days, and the cumulative incidence of alcohol relapse at 1 year was 70.2% (95% CI: 67.7, 72.7), which increased yearly during the follow-up period (Supplemental Table S4, http://links.lww.com/HC9/A686). Overall, 85% relapsed to hazardous drinking during the study period. After 6 months (landmarked time), patients with alcohol relapse had significantly lower long-term survival compared to patients without alcohol relapse, log-rank p<0.001 (Figure 1). Results were similar at 1-year landmark analysis (Supplemental Figure S2, http://links.lww.com/HC9/A688). No differences in survival were found between patients with slips and hazardous drinking (6 mo log-rank p=0.44; 1 y log-rank 0.36).
FIGURE 1.
Comparison of survival by alcohol relapse status at 6-month landmark. Time 0=6 months landmark time.
Univariable and multivariable competing risk analysis for factors associated with alcohol relapse can be found in Supplemental Table S5, http://links.lww.com/HC9/A686. On multivariable competing risk analysis, age [sHR 1.02 (95% CI: 1.01, 1.03), p<0.001] and AH presentation during the COVID-19 pandemic [sHR 1.97 (95% CI: 1.49, 2.61), p<0.001] were associated with an increased risk for alcohol relapse, whereas absence of hypertension [sHR 0.75 (95% CI: 0.59, 0.97), p=0.03], and MAUD [sHR 0.71 (95% CI: 0.56, 0.90), p=0.01] were associated with a lower risk for alcohol relapse.
Recurrent AH
The cumulative incidence of rAH over the study period can be found in Figure 2. During a 3055 person‐year follow‐up, 116 patients (8.8%) developed rAH at an annual incidence rate of 3.8% (95% CI: 2.8–4.8). There were no significant changes in the annual incidence of rAH during the study period (p=0.10). In patients with alcohol relapse, the rate of rAH was 21.9%, and the median (IQR) days from relapse to rAH was 468 (246, 1053). None of the patients with alcohol abstinence met biochemical criteria for rAH. The median (IQR) days to rAH hospitalization was 543 (311, 1164). Median (IQR) nadir total bilirubin between index AH hospitalization and rAH hospitalization was 1.2 (0.9, 1.9) mg/dL, and the median (IQR) days from index AH hospitalization to nadir total bilirubin was 176 (53, 335) days. Overall, the median % (IQR) increase of total bilirubin from interim nadir total bilirubin to rAH admission was 333% (230, 600). Two patients (1.7%) had a liver biopsy during rAH hospitalization.
FIGURE 2.
Cumulative incidence of recurrent alcohol-associated hepatitis during follow-up.
Comparisons of patient characteristics at index AH hospitalization stratified by subsequent development of rAH can be found in Table 1. Compared to patients who did not develop rAH, patients who developed rAH were significantly younger (44.8±9.9 vs. 48.2±10.9 y, p=0.002), were less likely to be married [25% (n=29) vs. 35.5% (n=427), p=0.02] and had lower median (IQR) MELD score [19.5 (17, 25.5) vs. 22 (18, 27), p=0.02]. Accordingly, patients with rAH had lower rates of severe AH, 45.7% (n=54) versus 58.5% (n=702) (p=0.01). There were no significant differences between the 2 groups in the distribution of sex, insurance type, use of depression/anxiety medications, liver-related complications, and median (IQR) daily alcohol intake (Table 1).
Comparisons of MAUD, alcohol rehabilitation, and gastroenterology/hepatology subspeciality clinic visit postdischarge stratified by subsequent development of rAH can be found in Table 2. Overall, the rates of MAUD were low and similar between the 2 groups [17.2% (n=20) in those with vs. 15.0% (n=180) in those without rAH], but median time to MAUD was longer in patients with rAH (397 vs. 163 d, p=0.06). Rates of alcohol rehabilitation were also low in both groups (Table 2), but the days to rehabilitation were significantly shorter in patients with rAH compared to patients without rAH [median (IQR) 21 (9, 191) vs. 236 (47, 603) days, p=0.01]. In addition, patients with rAH had higher rates of gastroenterology/hepatology subspeciality clinic visit postdischarge [61.2% (n=71) vs. 46.7% (n=561), p=0.003] but had similar times with regard to median days to clinic visit (Table 2).
TABLE 2.
Comparisons of MAUD, alcohol rehabilitation, and subspeciality clinic visit postdischarge between patients who developed recurrent AH and who did not
| Recurrent AH N=116 | No recurrence N=1201 | p | |
|---|---|---|---|
| Type of MAUD, n (%) | |||
| Any medication | 20 (17.2) | 172 (14.3) | 0.39 |
| Acamprosate | 4 (3.5) | 25 (2.1) | 0.39 |
| Baclofen | 7 (6.0) | 19 (1.6) | <0.001 |
| Gabapentin | 13 (11.2) | 141 (11.7) | 0.86 |
| Naltrexone | 5 (4.3) | 18 (1.5) | 0.03 |
| Topiramate | 1 (<0.1) | 14 (1.2) | 1.00 |
| Multiple | 5 (4.3) | 15 (1.2) | 0.15 |
| Median time to alcohol relapse | 278 (104, 588) | 103 (26, 459) | <0.001 |
| Median time to first fill of MAUD, days (IQR) | 397 (89, 1,357) | 163 (35, 646) | 0.06 |
| Alcohol rehabilitation, n (%) | 10 (8.6) | 67 (5.6) | 0.18 |
| Median time to alcohol rehabilitation | 21 (9, 191) | 236 (47, 603) | 0.01 |
| Number completing alcohol rehabilitation, n (%) | 8 (6.9) | 47 (3.9) | 0.24 |
| Gastroenterology/hepatology follow-up, n (%) | 71 (61.2) | 561 (46.7) | 0.003 |
| Median time to gastroenterology/hepatology subspeciality clinic visit, days (IQR) | 24 (10, 53) | 20 (9, 48) | 0.28 |
Abbreviations: AH, alcohol-associated hepatitis; IQR, interquartile range; MAUD, medications for alcohol use disorder.
After 1 year (landmarked time), the cumulative proportion surviving at 1 and 3 years was significantly lower in patients who developed rAH compared to patients who did not develop rAH: 1 year 75% versus 90% and 3 years 50% versus 78% (log-rank p<0.001) (Figure 3). Results were similar at 2-year landmark analysis (Supplemental Figure S3, http://links.lww.com/HC9/A689), where patients who developed rAH had significantly lower long-term survival compared to patients who did not develop rAH.
FIGURE 3.
Comparison of survival by recurrent AH status at 1-year landmark. Time 0=1 year landmark time. Abbreviation: AH, alcohol-associated hepatitis.
Comparisons of clinical characteristics between index AH hospitalization and rAH hospitalization in patients with rAH can be found in Table 3. There were no differences between index AH hospitalization and rAH hospitalization with regard to the median alcohol intake per day and use of depression/anxiety medications. However, at the time of rAH, there was a significant increase in the prevalence of underlying cirrhosis (91.6%; 13.6% increase from 77.6%), and patients were sicker with higher median MELD scores [22 (17, 27) vs. 19.5 (17, 25.5), p=0.02]. Accordingly, there were significantly higher rates of intensive care unit admission/transfer compared to the index AH hospitalization [25.9% (n=30) vs. 11.2% (n=13), p=0.004] and acute kidney injury [35.3% (n=41) vs. 21.6% (n=25), p=0.02]. After rAH hospitalization discharge, 14.6% (n=17) received MAUD and 6% (n=7) underwent alcohol rehabilitation. At the end of the study follow-up, 54.3% (n=63) died and 1 patient (0.9%) underwent LT.
TABLE 3.
Comparisons of patient clinical characteristics between index hospitalization and recurrent AH hospitalization (N=116)
| Index hospitalization | Recurrent hospitalization | p | |
|---|---|---|---|
| Age in years (mean, SD) | 44.8 (9.9) | 47.0 (10.1) | <0.001 |
| Anxiety medication, n (%) | 16 (13.8) | 13 (11.2) | 0.53 |
| Depression medication, n (%) | 14 (12.1) | 12 (10.3) | 0.62 |
| Underlying cirrhosis, n (%) | 90 (77.6) | 106 (91.4) | 0.001 |
| Hepatitis C, n (%) | 12 (10.3) | 12 (10.3) | 1.00 |
| Diabetes, n (%) | 13 (11.2) | 15 (12.9) | 0.53 |
| Hypertension, n (%) | 28 (24.1) | 15 (12.9) | 0.01 |
| Ascites, n (%) | 28 (24.1) | 26 (22.4) | 0.75 |
| HE, n (%) | 13 (11.2) | 22 (19.0) | 0.10 |
| Body mass index, median kg/m2 | 28.3 (6.8) | 27.7 (6.7) | 0.56 |
| Alcohol intake per day, median (IQR) grams | 112 (60, 350) | 84 (60, 224) | 0.10 |
| Laboratory results | |||
| White blood cell count, 109 | 10.2 (7.2, 14.8) | 7.9 (5.3, 11.2) | 0.003 |
| Sodium, mmol/L | 133 (129, 136) | 134 (129, 128) | 0.22 |
| Creatinine, mg/dL | 0.8 (0.6, 1.0) | 0.9 (0.6, 1.4) | 0.03 |
| AST, units/L | 140.5 (96, 205.5) | 132 (86.5, 209.5) | 0.49 |
| ALT, units/L | 39 (27, 58) | 41.5 (27.5, 58.5) | 0.33 |
| ALP, units/L | 185.5 (120.5, 236.5) | 160 (119.5, 208.5) | 0.34 |
| Total bilirubin, mg/dL | 7.4 (4.8, 14.3) | 7.0 (4.5, 14.5) | 0.58 |
| Albumin, g/dL | 2.8 (2.4, 3.1) | 3.0 (2.5, 3.4) | 0.03 |
| Prothrombin time, seconds | 18.0 (15.1, 21.1) | 19.7 (16.4, 24.3) | 0.003 |
| INR | 1.7 (1.4, 2.0) | 1.8 (1.5, 2.2) | 0.02 |
| MELD, median (IQR) | 19.5 (17, 25.5) | 22 (17, 27) | 0.02 |
| MDF, median (IQR) | 35.3 (20.7, 59.8) | 61.1 (42.8, 76.0) | 0.05 |
| SIRS, n (%) | 57 (49.6) | 40 (34.8) | 0.03 |
| MAP, median (%) | 92.0 (80.3, 104.0) | 89.5 (78.2, 100.0) | 0.32 |
| Severe AH, n (%) | 53 (45.7) | 65 (56.0) | 0.10 |
| Corticosteroid use, n (%) | 43 (37.1) | 40 (34.5) | 0.65 |
| Infection, n (%) | 42 (36.2) | 39 (33.6) | 0.66 |
| ICU admission, n (%) | 13 (11.2) | 30 (25.9) | 0.004 |
| Mechanical ventilation use, n (%) | 11 (9.5) | 13 (11.2) | 0.64 |
| Hemodialysis use, n (%) | 1 (0.9) | 3 (2.6) | 0.32 |
| Acute kidney injury, n (%) | 25 (21.6) | 41 (35.3) | 0.02 |
| GI bleed, n (%) | 34 (29.3) | 24 (20.7) | 0.10 |
| Alcohol withdrawal, n (%) | 16 (13.8) | 24 (20.7) | 0.10 |
| Peak bilirubin | 8.5 (5.3, 9.9) | 8.1 (5.2, 17.7) | 0.21 |
| Peak INR | 1.7 (1.5, 2.1) | 2.0 (1.6, 2.4) | 0.002 |
| Hospital length of stay, median (IQR) | 6 (4, 11) | 5 (3, 9) | 0.09 |
Abbreviations: AH, alcohol-associated hepatitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; GI, gastrointestinal; ICU, intensive care unit; INR, international normalized ratio; IQR, interquartile range; MAP, mean arterial pressure; MDF, Maddreys discriminant function; MELD, Model for End-stage Liver Disease; SIRS, systemic inflammatory response syndrome.
Univariate competing risk analysis for factors associated with rAH can be found in Supplemental Table S6, http://links.lww.com/HC9/A686. Age [sHR 0.98 (95% CI: 0.96, 1.00), p=0.02], Medicaid insurance [sHR 1.56 (95% CI: 1.03, 2.36), p=0.04], marital status [sHR 0.53 (95% CI: 0.35, 0.81), p=0.003], and MAUD [sHR 0.59 (95% CI: 0.36, 0.95), p=0.03] were associated with rAH risk. On multivariable competing risk analysis, marital status [sHR 0.54 (95% CI: 0.34, 0.92), p=0.01] and MAUD [sHR 0.56 (95% CI: 0.34, 0.91), p=0.02] were associated with a lower risk for rAH (Table 4).
TABLE 4.
Multivariable competing risk analysis for factors associated with recurrent AH
| Variable | sHR (95% CI) | p |
|---|---|---|
| Age (per year increase) | 0.99 (0.97, 1.00) | 0.11 |
| Medicaid insurance (ref: non-Medicaid) | 1.47 (0.97, 2.23) | 0.07 |
| Marital status (re: not married) | 0.54 (0.35, 0.83) | 0.01 |
| MAUDa | 0.54 (0.34, 0.92) | 0.02 |
| Follow-up with gastroenterology subspecialitya | 1.34 (0.91, 1.96) | 0.13 |
Time-dependent covariate.
Abbreviations: AH, alcohol-associated hepatitis; AUD, alcohol use disorder; sHR, subhazard ratio.
DISCUSSION
In this study of well-characterized patients with AH who survived their index hospitalization, the cumulative incidence of rAH was 8.8%, with an annual incidence rate of 3.8%. rAH is associated with significant morbidity and lower long-term survival compared to patients who did not develop rAH. Less than 20% of the patients received MAUD or participated in an alcohol rehabilitation program after the index AH hospitalization. Thus, most patients experienced alcohol relapse, which was associated with lower long-term survival, underscoring the importance of promoting and sustaining alcohol abstinence in this patient population.
Although MAUD was used infrequently in this cohort, its use was associated with a lower risk for rAH (and alcohol relapse). This finding is not unexpected since MAUD has been found to reduce the risk of hepatic decompensation in patients with ALD17–19 but also underutilized in ALD.20 Hence, early use of MAUD in survivors of AH could be a significant intervention that can prevent negative outcomes and prognosis in this patient population. However, due to sample size limitations, we were unable to investigate the association between the type of MAUD and rAH. In a recent study by Vannier and colleagues,17 naltrexone and gabapentin were associated with the lowest odds of hepatic decompensation in patients with concurrent AUD and ALD. However, the safety of these medications in AH, specifically naltrexone, which is contraindicated in severe liver disease,21 remains uncertain. Therefore, comparative randomized trials are required to elucidate the safety and efficacy of MAUD in patients with AH.
Contrary to the beneficial effects of MAUD, we did not find an association between alcohol rehabilitation and rAH or alcohol relapse. This finding is at odds with a previous study, which showed the benefit of early rehabilitation for reducing alcohol relapse in patients with AH.22 Potential reasons for this discrepancy could be related to the differences in sample sizes, type, and duration of rehabilitation, as well as unmeasured confounders such as patient attitudes toward alcohol rehabilitation.2,19,23–30 Nevertheless, our results highlight a key area where care could be substantially improved in patients with AH. Several strategies could improve the rates of delivering effective interventions to address AUD, including a multidisciplinary approach involving addiction specialists29 or navigational services led by social workers who can proactively engage in case management, service linkage, and provide motivational support.31
AUD substantially increased during the COVID-19 pandemic32 and correlating with these data, we found the pandemic to be associated with an increased risk for alcohol relapse. Interestingly, this association was not found with rAH. The reasons for this finding are unclear, and further studies with longer follow-up are warranted to understand the downstream impact of the pandemic on AH survivors. Furthermore, patients who are married are less likely to have rAH compared to nonmarried patients. This finding is supported by previous studies33–35 showing a reduced risk for AUD with marriage, which theoretically would reduce the risk for rAH.
Another important finding of our study was that though most patients relapsed to hazardous drinking, only a fraction developed rAH. One explanation for this is that the amount and duration of alcohol consumed previously is itself not sufficient for the development of AH.36 Other possible explanations include genetic predisposition (ie, patatin-like phospholipase domain-containing protein 3 polymorphisms), metabolic profile, and differential pathological responses to chronic alcohol use.37–39 Moreover, interestingly, one patient with severe rAH in our cohort received LT. A study by the American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis reported successful LT in patients with AH with prior hepatic decompensation, albeit these patients had harmful alcohol use (akin to the rAH population in this study) and lower post-LT survival compared to patients with AH presenting with their first decompensation.40 Overall, these data suggest pursuing LT for those who present with rAH is probably going to be far more challenging than for those presenting with their first episode of severe AH.
There are several limitations to this study. The incidence of rAH could have been underestimated as we could not account for rAH hospitalizations that occurred outside of our health care system (eg, admissions across state lines), nor AH events that could have occurred before the study period or were managed as outpatient. Similarly, “covert” alcohol relapse could have been missed as alcohol biomarkers were not routinely available. Moreover, although we used stringent criteria to define rAH based on expert consensus and NIAAA definitions for AH,3 there is no prior literature reporting on histological data to confirm if the diagnostic criteria for initial AH are valid for rAH. Hence, the potential of misclassification for rAH exists. Conversely, compared to a prior study,9 our stringent criteria for rAH plus the fact that the interim nadir total bilirubin between index hospitalization and rAH hospitalization was 1.2 mg/dL, which is significantly lower when compared to median total bilirubin of 7.0 mg/dL at the time of rAH hospitalization, ensured each rAH event was a discrete AH event. Hence, our study could provide a framework for future studies investigating rAH. Our study was also performed within a Midwestern US hospital system. Hence, it is not known whether our results could be extrapolated to other centers in the United States. A prospective multiregional study with standardized evaluation with biomarkers for alcohol use is needed to build on the findings of this study. Similarly, the majority of patients in our study were White. It is unclear how our findings would generalize to non-White populations with AH. Lastly, due to the retrospective nature of the study, residual confounding exists.
Despite these limitations, this study has several strengths. To our knowledge, this is the first US study and the largest study to date evaluating the incidence, clinical characteristics, risk factors, and outcomes associated with rAH and alcohol relapse in AH survivors. Our large sample allowed for meaningful demographic and clinical comparisons between patients who developed rAH and who did not. In addition, our study’s long-term follow-up allowed for appropriate risk assessment for rAH and alcohol relapse while accounting for death and LT as a competing risk. These assessments allow for a better understanding of the natural history of patients with AH and provide insight into key strategies, such as early administration of MAUD, which can improve outcomes in this patient population. Lastly, another strength of our study was the robustness employed to identify AH. It is well established that ICD-9/10 codes are not accurate for the identification of AH.41–43 For example, only 51% of patients with AH in this study had ICD-9/10 codes for AH. It was for this reason that we undertook a manual chart review of each patient’s record to confirm AH diagnosis, adding vigor to our study design.
In conclusion, ~1 in 10 patients with AH who survive their initial hospitalization develop rAH. rAH is associated with significant morbidity and lower long-term survival compared to patients who did not develop rAH. Although alcohol relapse was associated with lower long-term survival, a minority of patients received MAUD or rehab, and a majority experienced alcohol relapse. Comparative randomized clinical trials are direly needed to evaluate the safety and efficacy of MAUD for the prevention of alcohol relapse and rAH in AH survivors.
Supplementary Material
AUTHOR CONTRIBUTIONS
Kavish R. Patidar and Samer Gawrieh: study concept and design; Kavish R. Patidar and James E. Slaven: data analysis; Kavish R. Patidarand Samer Gawrieh: manuscript preparation; all authors: critical manuscript review.
CONFLICTS OF INTEREST
Eric S. Orman has consulted for Sitero and served on an advisory board for BioVie. Samer Gawrieh has consulted for TransMedics and Pfizer and received research grant support from Viking, Zydus, and Sonic Incytes. Naga Chalasani has paid consulting agreements with Madrigal, Zydus, Galectin, Foresite, Merck, GSK, Ventyx, Altimmune, and Pfizer. Naga Chalasani receives research support from DSM and Exact Sciences and has equity ownership in Avant Sante Therapeutics. The remaining authors have no conflicts to report.
Footnotes
Abbreviations: AH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; AUD, alcohol use disorder; ICD, International Classification of Diseases; INPC, Indiana Network for Patient Care; IQR, interquartile range; LT, liver transplant; MAUD, medications for alcohol use disorder; MELD, Model for End-stage Liver Disease; NIAAA, National Institute on Alcohol Abuse and Alcoholism; rAH, recurrent alcohol-associated hepatitis; sHR, subhazard ratio.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.hepcommjournal.com.
Contributor Information
Kavish R. Patidar, Email: kavish.patidar@bcm.edu.
Maria Guarnizo Ortiz, Email: maguar@iu.edu.
James E. Slaven, Email: jslaven@iu.edu.
Lauren D. Nephew, Email: lnephew@iu.edu.
Eduardo Vilar Gomez, Email: evilar@iu.edu.
Carla D. Kettler, Email: ckettler@iu.edu.
Marwan S. Ghabril, Email: mghabril@iu.edu.
Archita P. Desai, Email: desaiar@iu.edu.
Eric S. Orman, Email: esorman@iu.edu.
Naga Chalasani, Email: nchalasa@iu.edu.
Samer Gawrieh, Email: sgawrieh@iu.edu.
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